Bradykinin receptors of two classes are known. The B1 receptor (B1-BK) is not present in normal cells under normal conditions. In contrast, the B2-BK receptor is normally present on many cell types or tissues. Although the B1 receptor (B1-BK) is not present under normal conditions, its synthesis is induced in blood vessel muscular layers during inflammation.
Recent reports point to an important role of bradykinin B1 receptors in physiopathology. Dray and Perkins [Trends in Neurosci. 16, 99-104(1993)] have reviewed the possible implication of B1 receptors in various inflammatory states, in tissue reactions and in hyperalgesia. Alvarez et al. [Clin. Sci. 82, 513-519 (1992)] have provided evidence that B1 receptors are present in spontaneously hypertensive rats (SHR), and Regoli et al. [PCT application WO 98/07746] have provided evidence that inappropriate B1 receptor activity is associated with some forms of diabetes. In particular, it is known that capillary permeability is augmented in the streptozotocin diabetic rat model, and the vascular BK receptors of the portal veins of these animals have been shown to exhibit enhanced contractibility and capillary permeability in response to the B1-agonist desArg8BK. This effect was abolished by the B1-antagonist Lys[Leu]desArg9BK while the B2-antagonist HOE140 had no effect. A similar increased sensitivity to desArg9BK was observed in untreated SHR animals, prior to the establishment of hypertension, which was reversed by the same B1-antagonist. These results indicate that the B1-receptor is a target for a drug-preventive approach to diabetic or hypertensive vasculopathy.
Peptide antagonists of bradykinin receptors are known, although most reported antagonists have activity towards B2-receptors. There are to date very few small molecule B1 antagonists. It would be useful to have effective antagonists of the B1-BK receptor.